Septic shock is a serious medical condition that is caused by invasion of the circulatory system by bacteria. Septic shock is characterized by acute circulatory failure, usually with hypotension, followed by multiple organ failure and acute renal failure. The mortality rate of patients having septic shock is in the range of 25% to 90%. It is estimated that up to 500,000 people a year in both the United States and Europe develop septic shock.
The human immune system has many dedicated receptor systems that detect common pathogens, especially bacteria, and these receptor systems are distinct from the specific antibody and T-cell receptor systems, because they are permanently present, and are not tailored to meet a particular threat. Many of the dedicated receptor systems recognize the structural components of bacteria, such as lipopolysaccharide (LPS) lipoteichoic acid and peptidoglycan, and lead to activation of the immune system when these receptors bind structural components of bacteria.
LPS, a major component of the outer cell membrane of gram-negative bacteria, appears to be a major factor in the progression of a bacterial infection to septic shock. The principal mechanism for recognition by the human immune system of LPS is by binding of the CD14 receptor on macrophages to LPS. This binding requires LPS Binding Protein (LBP), an inducible protein made in the liver. Once macrophages have bound and recognized LPS, the macrophages produce massive amounts of inflammatory cytokines, especially tumor necrosis factor-.alpha.(TNF .alpha.), Interleukin 1 .beta.(IL- 1.beta.), and Interleukin 6 (IL-6).
Three of the transcription factors important in inducing LBP production in the liver are AP-1, C/EBP and STAT-3. All of these can be stimulated through the IL-6 signaling pathway, which is produced locally in the liver by Kuppfer cells. IL-6 stimulates the MAP kinases Mitogen-Activated Protein Kinases, also known as Extracellular Signal-Regulated Kinase or ERK, of which there are two isoforms (also called ERK1 and ERK2) through MEK, (the name given to MAP-kinase, namely Mitogen-Activated Protein Kinase Kinase), and these MAP kinases can activate the three transcription factors mentioned above by phosphorylation. Thus, an inhibitor of MEK can decrease the stimulation of LBP gene transcription, and attenuate the strength of the macrophage response to LPS.
In macrophages, LPS signaling appears to activate all three of the known MAP kinase pathways, including the MEK/ERK cascade, and LPS stimulation of macrophages leads to rapid and major activation of ERKs. ERK is believed to be one of the kinases that phosphorylates I.kappa.B, a prerequisite for the liberation of the transcription factor NF .kappa.B. NF .kappa.B, once liberated, enters the nucleus, and is probably the single most important transcriptional activator for production of TNF .alpha.. Thus, an inhibitor of MEK or ERK activity could also decrease the stimulation of TNF-.alpha. gene transcription, leading to a greatly decreased physiological response to LPS.
In cells that contain the TNF receptor, activation of that receptor leads to turning on of many pathways that lead to toxicity in the target cell, and which culminate in apoptosis (regulated self-destruction of the cell). Multiple organ failure is more likely caused by TNF-.alpha. induced toxicity than by any other single cause. Neutral sphingomyelinase has been shown to be activated by the TNF receptor, and this, in turn, activates ceramide-activated protein kinase, which then activates the MEK/MAP kinase pathway in the target cells, probably adding to the overall toxic effects of TNF.
Thus, the MEK/MAP kinase pathway is important in septic shock, and is involved at several vital points in the progression of septic shock.